The neurobiological basis of autism, mood disorders, psychotic syndromes, anxiety syndromes, dementia, mental retardation, motor dysfunction, and learning disability is poorly established, but these occur commonly as result of fetal, juvenile, and adult disorders of thyroid hormone level. The motor abnormalities in these disorders may be predicated on developmental abnormalities of the motor system and its connections with hippocampus and frontal lobe, which are primary fetal targets affected by thyroid hormone (TH,T4,T3) by poorly defined mechanisms. Two billion people worldwide are at risk for disorders of TH level because of iodine deficiency, thyroid gland toxins or maldevelopment. In the US, sporadic congenital hypothyroidism (SCH), which may have fetal hypothyroidism, occurs in 1/4000 live births. Despite early neonatal diagnosis and treatment of this disorder with T4, patients, particularly, but not limited to those with low T4 levels at birth, may have motor abnormalities and learning disabilities, perhaps related to irreversible fetal brain abnormalities. In humans and rodents, reduced TH causes neuropathological alterations in neuronal process growth and maintenance and connectivity. This occurs by affecting the cytoskeletal structures, the microtubules, microfilaments, and neurofilaments by selective effects on the transcription, translation, assembly, and axonal transport of their molecular components, i.e., tubulin isoforms, MAPS, actin, and neurofilaments. The hyt/hyt mouse has a fetal onset, severe and inherited hypothyroidism and is a model of severe human SCH. This mouse has specific reductions in certain tubulin isoform mRNAs and proteins, i.e., Mbeta5, Mbeta2, and Malpha1, found in pyramidal neurons of the fetal cerebral cortex (CC). These reductions may contribute to changes in microtubules and process growth and the observed alterations in reflexive and complex motor behavior related to corticospinal tract dysfunction.
The aims of this proposal are to use the hyt/hyt mouse compared to control euthyroid hyt/+ littermates and progenitor strain BALB/cBY mice: (1) to characterize the timing of corticospinal tract (from layer V sensorimotor cortex) growth to the spinal cord in the mouse neonate by tract tracing methodology; (2) to define the localization and potential abundance differences of Mbeta5 mRNA to layer V sensorimotor cortex pyramidal neurons in later gestation by in situ hybridization; and (3) to utilize tissue culture models of process growth and intact CC with molecular studies of Mbeta5 tubulin isoform mRNA/protein to define how TH regulates the development of CC motor neurons and motor behavior.
